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A Phase II Clinical Trial Evaluating the Efficacy and Safety of GDC-0449 in Children With Recurrent or Refractory Medulloblastoma

Phase 2
3 Years
21 Years
Open (Enrolling)
Recurrent Childhood Medulloblastoma

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Trial Information

A Phase II Clinical Trial Evaluating the Efficacy and Safety of GDC-0449 in Children With Recurrent or Refractory Medulloblastoma


I. Estimate the efficacy of GDC-0449 treatment for pediatric patients with recurrent or
refractory medulloblastoma, as measured by the sustained objective response rates for
patients without (stratum A) and with (stratum B) evidence of activation of Hedgehog (Hh)
signaling pathway in their tumors.

II. Characterize the pharmacokinetics (plasma) of GDC-0449 in children/adolescents with
refractory medulloblastoma.


I. Document and describe toxicities associated with GDC-0449 administered on a daily

II. Estimate the duration of objective response and progression-free survival (PFS).

III. Document pathologic and genomic methods to identify medulloblastomas with activation of
the Hh signaling pathway.

IV. Characterize the pharmacokinetics (cerebrospinal fluid) of GDC-0449 in
children/adolescents with refractory medulloblastoma.

OUTLINE: This is a multicenter study. Patients are stratified according to evidence of
activation of Hedgehog signaling pathway in their tumors (without vs with vs unknown).

Patients receive oral Hedgehog antagonist GDC-0449 once daily on days 1-28. Treatment
repeats every 28 days for up to 26 courses in the absence of disease progression or
unacceptable toxicity.

Plasma and cerebrospinal fluid samples are collected periodically for pharmacokinetic and
other correlative studies.

After completion of study treatment, patients are followed up for up to 12 months.

Inclusion Criteria:

- Patients with a histologically confirmed diagnosis of medulloblastoma that is
recurrent, progressive, or refractory to standard therapy and for which there is no
known curative therapy

- Patient has immunohistochemical (IHC) evidence of Hh pathway-activated tumor (stratum
B only)

- Patients must have bi-dimensionally measurable disease in the brain or spinal cord
defined as at least one lesion that can be accurately measured in at least 2 planes
in order to be eligible for this study

- Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to registration

- Patient must have adequate archival formalin-fixed, paraffin-embedded (FFPE) primary
tumor material for biology studies

- No CNS embryonal tumor other than medulloblastoma (patients with diagnosis of
atypical teratoid/rhabdoid tumor (ATRT), PNET from a non-cerebellar site within the
central nervous system, ependymoblastoma, or medulloepithelioma)

- Karnofsky performance status of ≥ 50% in patients > 16 years, or Lansky performance
status of ≥ 50% in patients ≥ 3 yrs and ≤ 16 years

- ANC ≥ 1,000 μL

- Platelet count ≥ 50,000/μL (transfusion independent)

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine 1.5 mg/dL

- Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age

- ALT ≤ 2.5 x institutional ULN for age

- AST ≤ 2.5 x institutional ULN for age

- Alkaline phosphatase ≤ 1.5 x institutional ULN

- Serum albumin ≥ 2.5 g/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use 2 forms of acceptable contraception, including one barrier
method, during and for 12 months after completion of study treatment

- 100% commitment to abstinence is considered an acceptable form of birth control

- Patients must have a BSA of ≥ 0.67 m^2 and at most 2.5 m^2

- No patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction)that
would compromise the patient's ability to tolerate protocol therapy or would likely
interfere with the study procedures or results

- No patients with inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy

- None of the following:

- Inability to swallow capsules

- Malabsorption syndrome or other condition that would interfere with enteral

- History of congestive heart failure

- History of ventricular arrhythmia requiring medication

- Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined
as less than the lower limit of normal for the institution despite adequate
electrolyte supplementation

- Clinically important history of liver disease, including viral or other
hepatitis or cirrhosis

- Male patients may not donate sperm during or for 12 months after completion of study

- Female patients may not donate ova while being treated with GDC-0449

- Patients may not donate blood for 12 months after completion of study treatment

- Patient must not be receiving warfarin

- Prior therapy will include primary therapy (including radiation therapy and
chemotherapy) and a maximum of 2 additional salvage therapies

- Patients can enroll on the protocol after failure on primary therapy

- Must have recovered from prior treatment-related toxicity

- No other myelosuppressive chemotherapy or immunotherapy within 4 weeks prior to study
entry (6 weeks if prior nitrosourea)

- Decadron dose should also be stable or decreasing for at least 1 week (7 days) prior
to starting therapy

- Radiotherapy: ≥ 3 months prior to study entry for craniospinal irradiation; ≥ 8 weeks
for local irradiation to primary tumor; ≥ 2 weeks prior to study entry for focal
irradiation for symptomatic metastatic sites

- Off all colony-stimulating factors > 1 week prior to study entry (G-CSF,GM-CSF,

- No patients receiving any other anticancer or investigational drug therapy

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response rates (partial and complete response)

Outcome Description:

Simon two-staged MinMax designs will be used to assess the rates of best objective response prior to progression.

Outcome Time Frame:

Up to 12 months

Safety Issue:


Principal Investigator

Amar Gajjar

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

November 2010

Completion Date:

Related Keywords:

  • Recurrent Childhood Medulloblastoma
  • Medulloblastoma



Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Stanford UniversityStanford, California  94305
Pediatric Brain Tumor ConsortiumMemphis, Tennessee  38105